After two comfortable wins the five-time major victor was growing in confidence, but she had no answers for Kerber, who is on a 12-match winning streak in a kind of comeback of her own after a sliding down the rankings previous year.
Maria Sharapova will take centre stage on Rod Laver Arena against Angelique Kerber in what is shaping as a fascinating encounter between the only two former Australian Open winners left in the women's draw.
Sharapova, back in Melbourne after testing positive for a banned substance here in 2016 resulting in a 15-month ban, had looked menacing in the opening two rounds.
Djokovic took a medical timeout in the second set to have his back and legs massaged but appeared to show little ill effects for the rest of the match.
Born in the same year of the Australian Open's debut at Melbourne Park, Kerber soaked up a birthday serenade from the terraces during her post-match interview on the court.
After serving a 15-month doping ban, Sharapova's much-hyped grand slam comeback was ended by Sevastova in a fourth-round epic at last year's US Open.
-Alexander "Sascha" Zverev says he's lost the crucial moments in his last three Grand Slams defeats. "I'm nearly dead", Halep said of the match which equaled Chanda Rubin's win over Arantxa Shanchez Vicario in 1996 - also 48 games - for the Australian Open record in terms of most games. "I just think the double-hander is easier".More news: White House slams Flake: He is looking for attention
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The German made only seven unforced errors in the 64-minute contest and, on the court celebrated victory with the look of a woman who firmly believes she is back in business.
Roger Federer and Novak Djokovic were nearly as ruthless in their straight-sets wins Saturday night, which is hardly surprising for two players with a combined 31 Grand Slam titles.
"I'm here because I'm motivated to get better at my craft".
In the next round, Garcia is scheduled to face Madison Keys of the United States, the 17th seed, who got the better of Romania's Ana Bogdan 6-3, 6-4.
Kyrgios is now the only Australian with a chance to take an Open singles title.
Men's seeds eliminated included No. 7 David Goffin and No. 13 Sam Querrey, who was beaten 6-4, 7-6 (6), 4-6, 6-2 by 80th-ranked Marton Fucsovics.
Djokovic goes forward to a third-round meeting with 21st seed Albert Ramos-Vinolas after the Spaniard defeated Tim Smyczek from America 6-4 6-2 7-6 (7-2).